Alzheimer's disease (AD) is a neurodegenerative process characterised by cognitive disorders associated with a progressive deterioration of the cholinergic function, and neuropathological lesions as senile plaques, formed by the fibrillary β-amyloid, and neurofibrillary tangles, bundles of paired helical filaments.
Generally speaking, AD is restricted to groups aged 60 years or more and is the most common cause of dementia in the elderly population. Today, AD affects 23 million people worldwide. As longevity increases, it is estimated that by the year 2050 the number of cases of AD will more than triplicate [Amaduci, L.; Fratiglioni, L. “Epidemiology of AD: Impact on the treatment”, in Alzheimer Disease: Therapeutic Strategies, E. Giacobini and R. Becker, Eds., Birhäuser, EEUU, 1994, pp. 8].
Two major histological lesions are observed in AD brains associated with the neuronal loss: neurofibrillary tangles and senile plaques at the intracellular and extracellular level respectively [“Alzheimer Disease: From molecular biology to therapy”, E. Giacobini and R. Becker, Eds., Birhäuser, EEUU, 1996].
Neurofibrillary tangles are structures formed by paired helical filaments (PHFs). They are comprised mainly of the microtubule-associated protein (MAP) tau in an abnormally hyperphosphorylated state [Grundke-Iqbal, I.; Iqbal, K.; Tung, Y. C.; Quinlan, M.; Wisniewski, H. M.; Binder, L. I., “Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology”, Proc. Natl. Acad. Sci. USA, 1986, 83, 4913-4917; Grundke-Iqbal, I.; Iqbal, K.; Quinlan, M.; Tung, Y. C.; Zaidi, M. S.; Wisniewski, H. M., “Microtubule-associated protein tau. A component of the Alzheimer paired helical filaments”, J. Biol. Chem., 1986, 261, 6084-6089; Greenberg, S. G.; Davies, P.; Schein, J. D.; Binder, L. I., “Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau.”, J. Biol. Chem., 1992, 267, 564-569]. Such aberrant phosphorylation of tau, determined by the effects of different protein kinases and phosphatases, appears to compromise on its ability to bind to and stabilise microtubules and this may contributes to AD pathology [Moreno, F. J.; Medina, M.; Perez, M.; Montejo de Garcini, E.; Avila, J., “Glycogen sintase kinase 3 phosphorylation of different residues in the presence of different factors: Analysis on tau protein”, FEBS Lett., 1995, 372, 65-68]. Thus, the blockade of this hyperphosphorylation step may be a prime target at which to interrupt the pathogenic cascade. The selective inhibitors of tau kinases might be new effective drugs for the treatment of AD.
The search for tau kinases inhibitors is a field of a great interest. Tau can be phosphorylated by several proline-directed protein kinases (PDKs) and non-PDKs. However, in AD the exact role of any of these kinases in the abnormal hyperphosphorylation of tau is not yet understood and to date, the activity of these kinases has not been found to be upregulated. It is no doubt that glycogen synthase kinase 3β (GSK-3β) is an in vivo tau kinase in the brain [Lovestone, S.; Hartley, C. L.; Pearce, J.; Anderton, B. H., “Phosphorylation of tau by glycogen synthase-3 in intact mammalian cells: the effects on the organization and stability of microtubules”, Neuroscience, 1996, 73, 1145-1157; Wagner, U.; Utton, M.; Gallo, J. M.; Miller, C. C., “Cellular phosphorylation of tau by GSK-3β influences tau binding to microtubules and microtubule organisation”, J. Cell. Sci., 1996, 109, 1537-1543; Ledesma, M.; Moreno, F. J.; Perez, M. M.; Avila, J., “Binding of apolipoprotein E3 to tau protein: effects on tau glycation, tau phosphorylation and tau-microtubule binding, in vitro”, Alzheimer Res., 1996, 2, 85-88]. These findings open the gate to the use of GSK-3β inhibitors as therapeutical agents in the treatment of AD. At the moment few compounds are known with this enzymatic inhibitory property.
Lithium behaves as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells Muñoz-Montaño, J. R.; Moreno, F. J.; Avila, J.; Diaz-Nido, J., “Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons”, FEBS Lett., 1997, 411, 183-188].
Finally, it is observed that insulin inactivates GSK-3 and it is shown that the non-dependent insulin diabetes mellitus is developed with the activation of this enzyme. So that, GSK-3 inhibitors would be a new therapy for the non-dependent insulin diabetes mellitus.
In our work team we have recently discovered a new family of small synthetic heterocyclic molecules with GSK-3β inhibitory properties at micromolar level.